All publications herein are incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference. The following description includes information that may be useful in understanding the present invention. It is not an admission that any of the information provided herein is prior art or relevant to the presently claimed invention, or that any publication specifically or implicitly referenced is prior art.
Pituitary tumor transforming gene (“PTTG1”), isolated from rat pituitary tumor cells (Pei and Melmed, 1997), was subsequently identified as a securin protein (Zou et al., 1999). PTTG1 is involved in several cellular processes (Vlotides et al., 2007), including human fetal brain development (Boelaert et al., 2003), telencephalic neurogenesis (Tarabykin et al., 2000) and rat liver regeneration (Akino et al., 2005). PTTG1-null mice exhibit testicular, splenic, pancreatic beta cell and pituitary hypoplasia (Wang et al., 2001b; Wang et al., 2003; Chesnokova et al., 2005). Disrupted PTTG1 results in male-selective insulinopenic diabetes in adult mice (Wang et al., 2003). PTTG1 is abundantly expressed in most cancers and enhanced PTTG1 correlates with tumor development and size (Saez et al., 1999; McCabe et al., 2003). PTTG1 is induced early in the pathogenesis of estrogen-induced rat prolactinomas (Heaney et al., 1999) and has been suggested as a prognostic marker for differentiated thyroid and breast cancer (Solbach et al., 2004), and colon cancer invasiveness and vascularity (Heaney et al., 2000). PTTG and HTLV-1 Tax exhibit co-operative transforming activity (Sheleg et al., 2007), while small interfering RNA (“siRNA”) directed against PTTG suppressed lung cancer growth in nude mice (Kakar and Malik, 2006) and was also suggested as a subcellular therapy for ovarian cancer (El-Naggar et al., 2007).
PTTG1 binds separase, inhibits cohesin cleavage and facilitates sister chromatid separation. Over-expressed PTTG1 resulted in chromosome instability and aneuploidy, which has been suggested as a mechanism underlying PTTG1 transforming activity (Wang and Melmed, 2000). PTTG1 inhibits p53 transcriptional activity (Bernal et al., 2002), and p53 stabilization is also uncoupled by loss of PTTG1 (Bernal and Hernandez, 2007). PTTG interacts with Ku, the regulatory subunit of DNA dependent protein kinase (Wang and Melmed, 2000; Pei, 2000; Pei, 2001; Chien and Pei, 2000), further indicating a role for the protein in DNA damage repair. PTTG1 also induces genetic instability in colorectal cancer cells by inhibiting double-stranded DNA repair activity (Kim et al., 2007), activates c-Myc (Pei, 2001) and bFGF (Chien and Pei, 2000), and promotes tumor angiogenesis (Zou et al., 1999; Kim et al., 2006). Dysregulated PTTG1 likely prevents mitotic exit as Cdc20 and PTTG1 double mutant embryos were unable to maintain metaphase arrest (Li et al., 2007). Although non-homologous end joining is intact in securin-deficient cells, the process occurs through aberrant end processing (Bernal et al., 2008). Using a ChIP-on-Chip assay, PTTG1 was shown to bind to multiple gene promoters (Tong et al., 2007), and PTTG1 binds to Sp1 and promotes the G1/S transition (Tong et al., 2007). This action may also contribute to PTTG1 induced cell transformation.
To further investigate PTTG1 functions, the inventors screened for PTTG1 interactions using a protein array comprising 5,000 proteins. They identified PTTG1 interacts with multiple proteins and showed that PTTG1 suppresses Aurora kinase A activity, Histone Deacetylase Inhibitor Responsiveness, as well as ROS-generating drug responsiveness in cancer treatment.